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1.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502300

RESUMO

Folate depletion causes chromosomal instability by increasing DNA strand breakage, uracil misincorporation, and defective repair. Folate mediated one-carbon metabolism has been suggested to play a key role in the carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. Methylenetetrahydrofolate reductase (MTHFR) is the enzyme catalyzing the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate that can control folate cofactor distributions and modulate the partitioning of intracellular one-carbon moieties. The association between MTHFR polymorphisms and HCC risk is inconsistent and remains controversial in populational studies. We aimed to establish an in vitro cell model of liver origin to elucidate the interactions between MTHFR function, folate status, and chromosome stability. In the present study, we (1) examined MTHFR expression in HCC patients; (2) established cell models of liver origin with stabilized inhibition of MTHFR using small hairpin RNA delivered by a lentiviral vector, and (3) investigated the impacts of reduced MTHFR and folate status on cell cycle, methyl group homeostasis, nucleotide biosynthesis, and DNA stability, all of which are pathways involved in DNA integrity and repair and are critical in human tumorigenesis. By analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that HCC cancer patients with higher MTHFR had a worse survival rate. The shRNA of MTHFR (shMTHFR) resulted in decreased MTHFR gene expression, MTHFR protein, and enzymatic activity in human hepatoma cell HepG2. shMTHFR tended to decrease intracellular S-adenosylmethionine (SAM) contents but folate depletion similarly decreased SAM in wildtype (WT), negative control (Neg), and shMTHFR cells, indicating that in cells of liver origin, shMTHFR does not exacerbate the methyl group supply in folate depletion. shMTHFR caused cell accumulations in the G2/M, and cell population in the G2/M was inversely correlated with MTHFR gene level (r = -0.81, p < 0.0001), MTHFR protein expression (r = -0.8; p = 0.01), and MTHFR enzyme activity (r = -0.842; p = 0.005). Folate depletion resulted in G2/M cell cycle arrest in WT and Neg but not in shMTHFR cells, indicating that shMTHFR does not exacerbate folate depletion-induced G2/M cell cycle arrest. In addition, shMTHFR promoted the expression and translocation of nuclei thymidine synthetic enzyme complex SHMT1/DHFR/TYMS and assisted folate-dependent de novo nucleotide biosynthesis under folate restriction. Finally, shMTHFR promoted nuclear MLH1/p53 expression under folate deficiency and further reduced micronuclei formation and DNA uracil misincorporation under folate deficiency. In conclusion, shMTHFR in HepG2 induces cell cycle arrest in G2/M that may promote nucleotide supply and assist cell defense against folate depletion-induced chromosome segregation and uracil misincorporation in the DNA. This study provided insight into the significant impact of MTHFR function on chromosome stability of hepatic tissues. Data from the present study may shed light on the potential regulatory mechanism by which MTHFR modulates the risk for hepatic malignancies.


Assuntos
Carcinoma Hepatocelular/patologia , Segregação de Cromossomos , DNA de Neoplasias/genética , Ácido Fólico/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Uracila/metabolismo , Apoptose , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Instabilidade Cromossômica , DNA de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Polimorfismo Genético , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
2.
PLoS One ; 16(4): e0250228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33930029

RESUMO

This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children's particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy.


Assuntos
Cognição/efeitos dos fármacos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Encéfalo/patologia , Sobreviventes de Câncer , Criança , Pré-Escolar , Imagem de Difusão por Ressonância Magnética/métodos , Progressão da Doença , Tratamento Farmacológico/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Antagonistas do Ácido Fólico/uso terapêutico , Genótipo , Humanos , Testes de Inteligência , Imageamento por Ressonância Magnética/métodos , Masculino , Metotrexato/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Descanso/fisiologia , Estudos Retrospectivos , Adulto Jovem , Proteínas tau/análise , Proteínas tau/líquido cefalorraquidiano
3.
Genes (Basel) ; 12(4)2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920562

RESUMO

Folate (vitamin B9) is found in some water-soluble foods or as a synthetic form of folic acid and is involved in many essential biochemical processes. Dietary folate is converted into tetrahydrofolate, a vital methyl donor for most methylation reactions, including DNA methylation. 5,10-methylene tetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate metabolism pathway that converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, which produces a methyl donor for the remethylation of homocysteine to methionine. MTHFR polymorphisms result in reduced enzyme activity and altered levels of DNA methylation and synthesis. MTHFR polymorphisms have been linked to increased risks of several pathologies, including cancer. Breast cancer, gliomas and gastric cancer are highly heterogeneous and aggressive diseases associated with high mortality rates. The impact of MTHFR polymorphisms on these tumors remains controversial in the literature. This review discusses the relationship between the MTHFR C677T and A1298C polymorphisms and the increased risk of breast cancer, gliomas, and gastric cancer. Additionally, we highlight the relevance of ethnic and dietary aspects of population-based studies and histological stratification of highly heterogeneous tumors. Finally, this review discusses these aspects as potential factors responsible for the controversial literature concerning MTHFR polymorphisms.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias da Mama/genética , Glioma/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Neoplasias Encefálicas/etnologia , Neoplasias Encefálicas/metabolismo , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Metilação de DNA , Feminino , Ácido Fólico/metabolismo , Predisposição Genética para Doença , Glioma/etnologia , Glioma/metabolismo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Neoplasias Gástricas/etnologia , Neoplasias Gástricas/metabolismo
4.
Aging (Albany NY) ; 13(8): 11352-11362, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33833133

RESUMO

BACKGROUND: Three polymorphisms in the Methylenetetrahydrofolate reductase (MTHFR) gene (C677T, A1298C, and A1793G) were reported associated with AD. However, their genotype distributions and associations with age at onset (AAO), homocysteine, and white matter lesions (WML) were unclear in the Chinese AD population. METHOD: We determined the presence of C677T, A1298C, and A1793G polymorphisms in the MTHFR gene using Sanger sequencing in a Chinese cohort comprising 721 AD patients (318 early-onset AD patients (EOAD) and 403 late-onset AD patients (LOAD)) and 365 elderly controls. Additionally, the homocysteine level and WML were evaluated in 121 AD patients. RESULTS: The frequency of allele T of C677T polymorphism was significantly higher in AD patients than in controls (P = 0.040), while no statistical difference was observed in A1298C and A1793G (P > 0.05). Besides, genotype distributions of C677T and A1298C polymorphisms statistically varied between AD patients and controls (P = 0.021, P = 0.012). Moreover, the AAO was significantly lower in CT/TT (C677T) genotypes carriers (P = 0.042) and higher in AC/CC (A1298C) and AG/GG (A1793G) genotypes carriers (P = 0.034, P = 0.009) in patients with LOAD. We also found that patients with CT/TT (C677T) genotypes were prone to present an increased homocysteine level (P = 0.036) and higher Fazekas score (P = 0.024). In comparison, patients with AG/GG genotypes (A1793G) had a significantly lower Fazekas score (P = 0.013). CONCLUSIONS: The genotype distributions of C677T and A1298C polymorphisms are associated with AD in the Chinese population. Moreover, AD patients with C677T polymorphism are prone to present an earlier onset, higher homocysteine level, and more severe WML.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Substância Branca/patologia , Idade de Início , Idoso , Alelos , Doença de Alzheimer/sangue , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Homocisteína/metabolismo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
5.
Am J Clin Nutr ; 113(5): 1361-1371, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33675351

RESUMO

BACKGROUND: Periconceptional folic acid (FA) supplementation is recommended to prevent the occurrence of neural tube defects. Currently, most over-the-counter FA supplements in Canada and the United States contain 1 mg FA and some women are prescribed 5 mg FA/d. High-dose FA is hypothesized to impair 1-carbon metabolism. We aimed to determine folate and 1-carbon metabolism biomarkers in pregnant women exposed to 1 mg or 5 mg FA. OBJECTIVES: This was an ancillary study within the Folic Acid Clinical Trial (FACT), a randomized, double-blinded, placebo-controlled, phase III trial designed to assess the efficacy of high-dose FA to prevent preeclampsia. METHODS: For FACT, women were randomized at 8-16 gestational weeks to receive daily 4.0 mg FA (high dose) or placebo (low dose) plus their usual supplementation (≤1.1 mg). Women were recruited from 3 Canadian FACT centers and provided nonfasting blood samples at 24-26 gestational weeks for measurement of RBC and serum total folate, serum unmetabolized FA (UMFA), tetrahydrofolate (THF), 5-methylTHF, 5-formylTHF, 5,10-methenylTHF, and MeFox (pyrazino-s-triazine derivative of 4α-hydroxy-5-methylTHF, a 5-methylTHF oxidation product); total vitamins B-12 and B-6; and plasma total homocysteine. Group differences were determined using χ2, Fisher exact, and Wilcoxon rank-sum tests. RESULTS: Nineteen (38%) women received high-dose FA and 31 (62%) received low-dose FA. The median RBC folate concentration was 2701 (IQR: 2243-3032) nmol/L and did not differ between groups. The high-dose group had higher serum total folate (median: 148.4 nmol/L, IQR: 110.4-181.2; P = 0.007), UMFA (median: 4.6 nmol/L, IQR: 2.5-33.8; P = 0.008), and 5-methylTHF (median: 126.6 nmol/L, IQR: 98.8-158.6; P = 0.03) compared with the low-dose group (median: 122.8 nmol/L, IQR: 99.5-136.0; median: 1.9 nmol/L, IQR: 0.9-4.1; median: 108.6 nmol/L, IQR: 96.4-123.2, respectively). Other biomarkers of 1-carbon metabolism did not differ. CONCLUSIONS: High-dose FA supplementation in early pregnancy increases maternal serum folate but not RBC folate concentrations, suggesting tissue saturation. Higher UMFA concentrations in women receiving high-dose FA supplements suggest that these doses are supraphysiologic but with no evidence of altered 1-carbon metabolism.


Assuntos
Suplementos Nutricionais , Ácido Fólico/administração & dosagem , Ácido Fólico/farmacologia , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/farmacologia , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Polimorfismo de Nucleotídeo Único , Gravidez
6.
Biol Pharm Bull ; 44(2): 162-168, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518670

RESUMO

Folic acid (FA) affect human physiology and drug metabolism. Up to now, the effect of microgravity on the pharmacokinetics of FA remains unclear. The pharmacokinetics of FA in Sprague-Dawley (SD) rats are laying a foundation for safe medicine administration of astronauts. Proteins expression of such FA metabolic enzymes as Methyltetrahydrofolate reductase (MTHFR), Cystathionine beta synthase (CBS) and Methionine synthase (MS) in a variety of organs was analyzed with Western-Blot, and mRNA expression was detected by RT-PCR. The plasma concentration-time profile of FA in normal or tail-suspended SD rats was acquired by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after oral administration of FA. Area under curve (AUC) and Cmax of FA in SD rats decreased significantly with extending period of tail-suspension. In terms of expressed level of metabolic enzymes over four suspension terms, as well as the level of the corresponding mRNAs, the following regularities were found: an obvious sharp decline of MTHFR tissue in kidney, a time-dependent increase of CBS in liver tissue and duodenum tissues, the resemblance of MS fluctuation to that of CBS in tested tissues. A four-week simulated microgravity of SD rats exhibits an unequivocal diminish of bioavailability of FA, and simulated microgravity shows a varying effect on the expression of FA-metabolizing enzyme in a variety of tissues.


Assuntos
Ácido Fólico/farmacocinética , Fenômenos Fisiológicos da Nutrição , Voo Espacial , Vitaminas/farmacocinética , Simulação de Ausência de Peso , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Animais , Cistationina beta-Sintase/metabolismo , Ácido Fólico/administração & dosagem , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Modelos Animais , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos Específicos , Vitaminas/administração & dosagem
7.
PLoS One ; 16(1): e0245005, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33411826

RESUMO

Epigenetics are known to be involved in various disorders, including neurobiological disorders like autism. Dietary factors such as folic acid can affect epigenetic marks using methylenetetrahydrofolate reductase (MTHFR) to metabolize folic acid to a one-carbon methyl group. As MTHFR mutations are frequent, it is curious as to whether excess folic acid, with or without functioning MTHFR, could affect gene expression, epigenetics, and neuromorphology. Here, we investigated gene expression and activity of epigenetic modifying enzymes, genome-wide DNA methylation, histone 3 modifications, and dendritic spine densities in SH-SY5Y cells with or without a knockdown of MTHFR and with or without an excess of folic acid. We found alterations to gene expression of epigenetic modifying enzymes, including those associated with disorders like autism. Grouping the epigenetic modifying enzymes by function indicated that gene expression was widely affected for genes that code for enzymes affecting DNA methylation, histone acetylation, histone methylation, histone phosphorylation, and histone ubiquitination when excess folic acid treatment occurred with or without the knockdown of MTHFR. MTHFR was significantly reduced upon excess folic acid treatment whether MTHFR was knocked-down or not. Further, methyl-CpG binding protein 2 expression was significantly decreased with excess folic acid treatment with and without proper MTHFR expression. Global DNA methylation decreased due to the knockdown alone while global hydroxymethylated DNA increased due to the knockdown alone. TET2 expression significantly increased with the MTHFR knockdown alone. Excess folic acid alone induced a decrease in TET3 expression. Excess folic acid induced an increase in dendritic spines without the MTHFR knockdown, but folic acid induced a decrease in dendritic spines when MTHFR was knocked-down. The knockdown alone also increased the dendritic spines significantly. Histone 3 acetylation at lysine 18 was significantly increased when excess folic acid was applied to cells with the MTHFR knockdown, as was histone 3 phosphorylation at serine 10. Broadly, our results indicate that excess folic acid, even with functioning MTHFR, could have detrimental effects on cells.


Assuntos
Metilação de DNA , Espinhas Dendríticas/patologia , Epigênese Genética , Ácido Fólico/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Neuroblastoma/patologia , Espinhas Dendríticas/metabolismo , Código das Histonas , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Células Tumorais Cultivadas , Complexo Vitamínico B/farmacologia
8.
Reprod Biol Endocrinol ; 19(1): 5, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33407572

RESUMO

BACKGROUND: The etiology between homocysteine and polycystic ovary syndrome (PCOS) is unclear. In humans, the level of homocysteine is mainly affected by two enzymes: methylene tetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR). While the activity of these two enzymes is mainly affected by three missense mutations, namely C677T (MTHFR), A1298C (MTHFR), and A66G (MTRR). This study aims to examine the association between the three missense mutations and PCOS and investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level. METHODS: A case-control study was designed, comprising 150 people with PCOS and 300 controls. Logistic regression analysis was used to assess the association between the three missense mutations and PCOS. Linear regression analysis was used to assess the association between the three missense mutations and the homocysteine level. Mediation analysis was used to investigate whether the three missense mutations exerted their effect on PCOS by affecting the homocysteine level. RESULTS: Following adjustments and multiple rounds of testing, MTHFR A1298C was found to be significantly associated with PCOS in a dose-dependent manner (compared to AA, OR = 2.142 for AC & OR = 3.755 for CC; P < 0.001). MTRR A66G was nominally associated with PCOS. Mutations in MTHFR A1298C and MTRR A66G were significantly associated with the homocysteine level. Mediation analysis suggested the effect of MTHFR A1298C on PCOS was mediated by homocysteine. CONCLUSIONS: MTHFR A1298C and MTRR A66G were associated with PCOS, and MTHFR A1298C might affect the risk of PCOS by influencing the homocysteine level.


Assuntos
Ferredoxina-NADP Redutase/genética , Predisposição Genética para Doença/genética , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação de Sentido Incorreto , Síndrome do Ovário Policístico/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Ferredoxina-NADP Redutase/metabolismo , Frequência do Gene , Genótipo , Homocisteína/metabolismo , Humanos , Desequilíbrio de Ligação , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Síndrome do Ovário Policístico/enzimologia , Síndrome do Ovário Policístico/etnologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
9.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440639

RESUMO

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway, and its loss of function through polymorphisms is often associated with human conditions, including cancer, congenital heart disease, and Down syndrome. MTHFR is also required in the maintenance of heterochromatin, a crucial determinant of genomic stability and precise chromosomal segregation. Here, we characterize the function of a fission yeast gene met11+, which encodes a protein that is highly homologous to the mammalian MTHFR. We show that, although met11+ is not essential for viability, its disruption increases chromosome missegregation and destabilizes constitutive heterochromatic regions at pericentromeric, sub-telomeric and ribosomal DNA (rDNA) loci. Transcriptional silencing at these sites were disrupted, which is accompanied by the reduction in enrichment of histone H3 lysine 9 dimethylation (H3K9me2) and binding of the heterochromatin protein 1 (HP1)-like Swi6. The met11 null mutant also dominantly disrupts meiotic fidelity, as displayed by reduced sporulation efficiency and defects in proper partitioning of the genetic material during meiosis. Interestingly, the faithful execution of these meiotic processes is synergistically ensured by cooperation among Met11, Rec8, a meiosis-specific cohesin protein, and the shugoshin protein Sgo1, which protects Rec8 from untimely cleavage. Overall, our results suggest a key role for Met11 in maintaining pericentromeric heterochromatin for precise genetic inheritance during mitosis and meiosis.


Assuntos
Segregação de Cromossomos , Meiose , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Mitose , Schizosaccharomyces/enzimologia , Schizosaccharomyces/genética , Alelos , Biomarcadores , Genótipo , Heterocromatina/genética , Heterocromatina/metabolismo , Humanos , Meiose/genética , Mitose/genética , Mutação , Fenótipo
10.
Ann Hum Biol ; 48(1): 62-65, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33455465

RESUMO

Type 2 diabetes mellitus (T2DM) susceptibility has increased due to the independent risks of genetic polymorphism and obesity as well as combinations of these. Despite recent advancements in T2DM management and diagnosis, the challenges of susceptibility and prognosis still remain. The present work is attempted to understand the association of methylenetetrahydrofolate reductase (MTHFR) (rs1801133) and FTO (rs9939609) genetic polymorphisms and obesity with T2DM among the Bengalee Hindu caste population of West Bengal, India. One hundred and four clinically diagnosed T2DM male patients and 176 healthy males, without family history of T2DM, (control group) of the endogamous linguistic group (Bengalee Hindu caste) participated. Genotyping was performed using the PCR-RFLP method following the isolation of genomic DNA. MTHFR (rs1801133) genetic polymorphism with CT genotype revealed significantly higher risk (OR = 3.44; p = .01) of T2DM compared to the CC genotype. The attenuation of MTHFR-T2DM risk after adjustment for age and waist circumference revealed obesity and age effects in progression of T2DM. T2DM patients also had significantly (p < .05) higher overall obesity, central obesity, and SBP compared to the controls. However, FTO (rs9939609) genetic polymorphism demonstrated no significant (p= .854) effect on T2DM and obesity. The present study identified that MTHFR genetic polymorphism and obesity might be used as screening tools for early prognosis of T2DM.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Diabetes Mellitus Tipo 2/complicações , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Obesidade/genética , Polimorfismo Genético , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Humanos , Índia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Adulto Jovem
11.
Aging (Albany NY) ; 13(1): 1176-1185, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33290257

RESUMO

5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare hereditary disease characterized by defects in folate and homocysteine metabolism. Individuals with inherited MTHFR gene mutations have a higher tendency to develop neurodegeneration disease as Alzheimer' disease and atherosclerosis. MTHFR is a rate-limiting enzyme catalyzing folate production, various SNPs/mutations in the MTHFR gene have been correlated to MTHFR deficiency. However, the molecular mechanisms underpinning the pathogenic effects of these SNPs/mutations have not been clearly understood. In the present study, we reported a severe MTHFR deficiency patient with late-onset motor dysfunction and sequenced MTHFR gene exons of the family. The patient carries an MD-associating SNP (rs748289202) in one MTHFR allele and the rs545086633 SNP with unknown disease relevance in the other. The rs545086633 SNP (p.Leu439Pro) results in an L439P substitution in MTHFR protein, and drastically decreases mutant protein expression by promoting proteasomal degradation. L439 in MTHFR is highly conserved in vertebrates. Our study demonstrated that p.Leu439Pro in MTHFR is the first mutation causing significant intracellular defects of MTHFR, and rs545086633 should be examined for the in-depth diagnosis and treatment of MD.


Assuntos
Homocistinúria/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Espasticidade Muscular/genética , Adolescente , Alelos , Ataxia/fisiopatologia , Baclofeno/uso terapêutico , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Feminino , Ácido Fólico/análogos & derivados , Ácido Fólico/uso terapêutico , Homocistinúria/diagnóstico , Homocistinúria/tratamento farmacológico , Homocistinúria/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Metionina/uso terapêutico , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Hipertonia Muscular/tratamento farmacológico , Hipertonia Muscular/fisiopatologia , Relaxantes Musculares Centrais/uso terapêutico , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/tratamento farmacológico , Espasticidade Muscular/fisiopatologia , Mutação de Sentido Incorreto , Condução Nervosa , Polimorfismo de Nucleotídeo Único , Complexo de Endopeptidases do Proteassoma , Proteólise , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/genética , Transtornos Psicóticos/fisiopatologia , Reflexo Anormal/fisiologia , Coluna Vertebral/diagnóstico por imagem , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/uso terapêutico
12.
BMC Med ; 18(1): 318, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33172445

RESUMO

BACKGROUND: Genome-wide and clinical studies have linked the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension. METHODS: Observational data on 6076 adults of 18-102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008-2012 using standardised methods. RESULTS: The variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34-6.68; P = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes (P < 0.027). CONCLUSIONS: The MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Riboflavina/metabolismo , Idoso , Anti-Hipertensivos/uso terapêutico , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
13.
Medicine (Baltimore) ; 99(40): e21962, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019388

RESUMO

To evaluate the association between gene polymorphisms of MTHFR (C677T, A1298C) and MTRR (A66G), and the recurrent spontaneous abortion (RSA) risk in Asia.Related case-control studies were collected, selected, and screened. A meta-analysis was conducted by Stata 12.0 software to assess the association between polymorphisms of target genes and RSA.Altogether 30 studies examining the relationship between genetic polymorphism of folate metabolism and RSA risk were included, among which 20 studies were related to MTHFR C677T, 11 to MTHFR A1298C and 6 to MTRR A66G. The studies suggested that MTHFR C677T polymorphism was closely connected with RSA risk under all models (P < .05). Furthermore according to the subgroup analysis of ethnicity, the correlation between C677T polymorphism and RSA was stronger in north of China when compared with south of China and other Asian countries (P > . 05). For MTHFR A1298C, it was closely related to RSA risk in all gene models except for (AC vs AA) (P < .05). However, when it comes to MTRR A66G, there was no significant correlation between gene A66G polymorphism and RSA risk except for the additive gene model (G vs A) (P < .05).The present evidence shows that the correlation between gene polymorphisms and RSA risk can be found in MTHFR C677T, A1298C (except for heterozygote model) and MTRR A66G (only in additive genotypes), and the detection of the correlated gene polymorphisms mentioned above is of certain guiding significance for preventing RSA and screening high-risk groups.


Assuntos
Aborto Habitual/genética , Ferredoxina-NADP Redutase/metabolismo , Ácido Fólico/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , China , Feminino , Humanos , Estudos Observacionais como Assunto , Polimorfismo de Nucleotídeo Único , Gravidez , Medição de Risco
14.
Genet Test Mol Biomarkers ; 24(11): 717-722, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33121283

RESUMO

Objective: Although genetic variants of key enzymes in the folic acid-methionine metabolic circulation, including methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) were thought to be related to the risk of recurrent pregnancy loss (RPL), the results of recent studies have been inconsistent. Therefore, the present retrospective case-control study was designed to explore whether the variants c.66A>G in MTRR and c.677C>T and c.1298A>C in MTHFR are associated with the susceptibility of RPL in Southeast Chinese women. Materials and Methods: In total, samples from 237 RPL patients and 618 healthy controls were collected and genotyped by fluorescent quantitative polymerase chain reaction. The frequencies of the variants were calculated and compared between the two groups. The relative risk of the various genotypes was further determined by calculating the odds ratio (OR) at a 95% confidence interval (CI). Results: A significant positive correlation was observed between the variants MTHFR c.677C>T, MTHFR c.1298A>C, MTRR c.66A>G, and RPL susceptibility (MTHFR c.677C>T, OR = 0.74, 95% CI = 0.58-0.95, p = 0.02; MTHFR c.1298A>C, OR = 1.39, 95% CI = 1.09-1.77, p = 0.008; MTRR c.66A>G, OR = 1.38, 95% CI = 1.10-1.73, p = 0.006). Further analysis of the genotypic distributions of the three variants between the two groups showed that the MTHFR c.677C>T heterozygote was associated with lower RPL risk, while the MTHFR c.1298A>C variant and MTRR c.66A>G heterozygote were correlated with higher RPL risk (dominant model, MTHFR c.677C>T, OR = 0.70, 95% CI = 0.52-0.95, p = 0.02; MTHFR c.1298A>C, OR = 1.39, 95% CI = 1.03-1.88, p = 0.032; MTRR c.66A>G, OR = 1.62, 95% CI = 1.20-2.19, p = 0.002). Conclusion: MTHFR c.677C>T and c.1298A>C and MTRR c.66A>G were associated with RPL in Southeast Chinese women.


Assuntos
Aborto Espontâneo/genética , Ferredoxina-NADP Redutase/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Aborto Habitual/genética , Aborto Espontâneo/metabolismo , Adolescente , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Estudos Retrospectivos
15.
J Biol Chem ; 295(47): 16037-16057, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-32934008

RESUMO

Methylenetetrahydrofolate reductase (MTHFR) links the folate cycle to the methionine cycle in one-carbon metabolism. The enzyme is known to be allosterically inhibited by SAM for decades, but the importance of this regulatory control to one-carbon metabolism has never been adequately understood. To shed light on this issue, we exchanged selected amino acid residues in a highly conserved stretch within the regulatory region of yeast MTHFR to create a series of feedback-insensitive, deregulated mutants. These were exploited to investigate the impact of defective allosteric regulation on one-carbon metabolism. We observed a strong growth defect in the presence of methionine. Biochemical and metabolite analysis revealed that both the folate and methionine cycles were affected in these mutants, as was the transsulfuration pathway, leading also to a disruption in redox homeostasis. The major consequences, however, appeared to be in the depletion of nucleotides. 13C isotope labeling and metabolic studies revealed that the deregulated MTHFR cells undergo continuous transmethylation of homocysteine by methyltetrahydrofolate (CH3THF) to form methionine. This reaction also drives SAM formation and further depletes ATP reserves. SAM was then cycled back to methionine, leading to futile cycles of SAM synthesis and recycling and explaining the necessity for MTHFR to be regulated by SAM. The study has yielded valuable new insights into the regulation of one-carbon metabolism, and the mutants appear as powerful new tools to further dissect out the intersection of one-carbon metabolism with various pathways both in yeasts and in humans.


Assuntos
Trifosfato de Adenosina/química , Metilenotetra-Hidrofolato Redutase (NADPH2)/química , S-Adenosilmetionina/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/enzimologia , Trifosfato de Adenosina/genética , Trifosfato de Adenosina/metabolismo , Regulação Alostérica , Humanos , Metilação , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , S-Adenosilmetionina/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
16.
Med Sci Monit ; 26: e920320, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32675800

RESUMO

BACKGROUND The C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism has been associated with hypertension and coronary heart disease, but its relationship with carotid artery remains unknown. This study aimed to investigate the association between the C677T polymorphism of the MTHFR gene in patients with confirmed carotid artery atherosclerosis. MATERIAL AND METHODS This retrospective study included 210 patients with carotid artery atherosclerosis (the patient group) and 210 controls (the control group). Color Doppler ultrasound was used to identify carotid artery intimo-medial thickness and atherosclerotic plaques. Sanger sequencing using the polymerase chain reaction (PCR) was used to detect the MTHFR C677T gene polymorphism. Systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), glycosylated hemoglobin (HbA1c), and other laboratory indicators were measured. RESULTS SBP, DBP, FPG, TC, LDL-C, HbA1c, and intimo-medial thickness were significantly increased in the patient group compared with the control group, and HDL-C was significantly lower. The allele frequencies of the C667T locus of MTHFR gene were significantly different between the two groups (P<0.05), and the TT genotype and the T allele frequencies in the patient group were higher than in the control group. Logistic regression analysis showed that SBP, TC, LDL-C, and the C667T MTHFR gene polymorphism were risk factors for carotid artery atherosclerosis. CONCLUSIONS The C677T polymorphism of the MTHFR gene was expressed in patients with carotid artery atherosclerosis.


Assuntos
Doenças das Artérias Carótidas/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Idoso , Aterosclerose/genética , Pressão Sanguínea/genética , Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/metabolismo , Artéria Carótida Primitiva/metabolismo , China/epidemiologia , Feminino , Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Hipertensão/genética , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Fatores de Risco
17.
J Exp Clin Cancer Res ; 39(1): 131, 2020 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-32653028

RESUMO

BACKGROUND: Esophageal cancer (EC) represents one of the most aggressive digestive neoplasms globally, with marked geographical variations in morbidity and mortality. Chemoprevention is a promising approach for cancer therapy, while acquired chemoresistance is a major obstacle impeding the success of 5-fluorouracil (5-FU)-based chemotherapy in EC, with the mechanisms underlying resistance not well-understood. In the present study, we focus on exploring the role of long non-coding RNA (lncRNA) HOTAIR in EC progression and sensitivity of EC cells to 5-FU. METHODS: Paired cancerous and pre-cancerous tissues surgically resected from EC patients were collected in this study. Promoter methylation of the MTHFR was assessed by methylation-specific PCR. RIP and ChIP assays were adopted to examine the interaction of DNA methyltransferases (DNMTs) with lncRNA HOTAIR and MTHFR, respectively. EC cells resistant to 5-FU were induced by step-wise continuous increasing concentrations of 5-FU. The sensitivity of EC cells to 5-FU in vivo was evaluated in nude mice treated with xenografts of EC cells followed by injection with 5-FU (i.p.). RESULTS: We found reciprocal expression patterns of lncRNA HOTAIR and MTHFR in EC tissues and human EC cells. Interference with lncRNA HOTAIR enhanced 5-FU-induced apoptosis, exhibited anti-proliferative activity, and reduced promoter methylation of the MTHFR in EC cells. Besides, overexpression of MTHFR attenuated the acquired chemoresistance induced by overexpression of lncRNA HOTAIR in EC cells. At last, enhanced chemosensitivity was observed in vivo once nude mice xenografted with lncRNA HOTAIR-depleted EC cells. CONCLUSION: Together, our study proposes that pharmacologic targeting of lncRNA HOTAIR sensitizes EC cells to 5-FU-based chemotherapy by attenuating the promoter hypermethylation of the MTHFR in EC.


Assuntos
Metilação de DNA , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/tratamento farmacológico , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , RNA Longo não Codificante/genética , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/química , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Nutrients ; 12(6)2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32521649

RESUMO

Fifteen to 20% of pregnant women may exceed the recommended intake of folic acid (FA) by more than four-fold. This excess could compromise neurocognitive and motor development in offspring. Here, we explored the impact of an FA-supplemented diet (5× FASD, containing five-fold higher FA than recommended) during pregnancy on brain function in murine offspring, and elucidated mechanistic changes. We placed female C57BL/6 mice for one month on control diets or 5× FASD before mating. Diets were maintained throughout pregnancy and lactation. Behavioural tests were conducted on 3-week-old pups. Pups and mothers were sacrificed at weaning. Brains and livers were collected to examine choline/methyl metabolites and immunoreactive methylenetetrahydrofolate reductase (MTHFR). 5× FASD led to hyperactivity-like behavior and memory impairment in 3-week-old pups of both sexes. Reduced MTHFR protein in the livers of FASD mothers and male pups resulted in choline/methyl metabolite disruptions in offspring liver (decreased betaine) and brain (decreased glycerophosphocholine and sphingomyelin in male pups, and decreased phosphatidylcholine in both sexes). These results indicate that moderate folate supplementation downregulates MTHFR and alters choline/methyl metabolism, contributing to neurobehavioral alterations. Our findings support the negative impact of high FA on brain development, and may lead to improved guidelines on optimal folate levels during pregnancy.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Suplementos Nutricionais , Ácido Fólico/administração & dosagem , Ácido Fólico/efeitos adversos , Fígado/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Recomendações Nutricionais , Caracteres Sexuais , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Troca Materno-Fetal , Transtornos da Memória/induzido quimicamente , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/metabolismo , Gravidez , Esfingomielinas/metabolismo
19.
Biomolecules ; 10(6)2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32512924

RESUMO

We explored the significance of the L-Arginine/asymmetric dimethylarginine (L-Arg/ADMA) ratio as a biomarker of endothelial dysfunction in stroke patients. To this aim, we evaluated the correlation, in terms of severity, between the degree of endothelial dysfunction (by L-Arg/ADMA ratio), the methylene tetrahydrofolate reductase (MTHFR) genotype, and the interatrial septum (IAS) phenotype in subject with a history of stroke. Methods and Results: L-Arg, ADMA, and MTHFR genotypes were evaluated; the IAS phenotype was assessed by transesophageal echocardiography. Patients were grouped according to the severity of IAS defects and the residual enzymatic activity of MTHFR-mutated variants, and values of L-Arg/ADMA ratio were measured in each subgroup. Of 57 patients, 10 had a septum integrum (SI), 38 a patent foramen ovale (PFO), and 9 an ostium secundum (OS). The L-Arg/ADMA ratio differed across septum phenotypes (p ≤ 0.01), and was higher in SI than in PFO or OS patients (p ≤ 0.05, p ≤ 0.01, respectively). In the PFO subgroup a negative correlation was found between the L-Arg/ADMA ratio and PFO tunnel length/height ratio (p ≤ 0.05; r = - 0.37; R2 = 0.14). Interestingly, the L-Arg/ADMA ratio varied across MTHFR genotypes (p ≤ 0.0001) and was lower in subgroups carrying the most impaired enzyme with respect to patients carrying the conservative MTHFR (p ≤ 0.0001, p ≤ 0.05, respectively). Consistently, OS patients carried the most dysfunctional MTHFR genotypes, whereas SI patients the least ones. Conclusions: A low L-Arg/ADMA ratio correlates with impaired activity of MTHFR and with the jeopardized IAS phenotype along a severity spectrum encompassing OS, PFO with long/tight tunnel, PFO with short/large tunnel, and SI. This infers that genetic MTHFR defects may underlie endothelial dysfunction-related IAS abnormalities, and predispose to a cryptogenic stroke. Our findings emphasize the role of the L-Arg/ADMA ratio as a reliable marker of stroke susceptibility in carriers of IAS abnormalities, and suggest its potential use both as a diagnostic tool and as a decision aid for therapy.


Assuntos
Septo Interatrial/metabolismo , Endotélio Vascular/metabolismo , AVC Isquêmico/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Adulto , Septo Interatrial/patologia , Endotélio Vascular/patologia , Genótipo , Humanos , AVC Isquêmico/diagnóstico , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
Nutrients ; 12(6)2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32471241

RESUMO

We examined the association between high-density lipoprotein cholesterol (HDL-C), and exercise and vegetarian diets, in Taiwanese adults, based on the Methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism. Using regression models, we analyzed historical data collected from 9255 Taiwan Biobank (TWB) participants from 2008 through 2015. Exposure to exercise was associated with higher HDL-C (ß = 1.0508 and 1.4011 for GG and GA + AA individuals, respectively), whereas a vegetarian diet was associated with lower HDL-C (ß = -6.2793 and -4.6359 for those with GG and GA + AA genotype, respectively). We found an interaction between exercise and diet among GG individuals (p = 0.0101). Compared with no exercise/no vegetarian diet, vegetarian diet/no exercise was associated with a 5.1514 mg/dl reduction in HDL-C among those with GG genotype (ß = -5.1514, p < 0.0001) and a 4.8426 mg/dl reduction (ß = -4.8426, p < 0.0001) among those with GA + AA genotype. Vegetarian diets in combination with exercise predicted a 6.5552 mg/dl reduction in HDL-C among GG individuals (ß = -6.5552) and a 2.8668 mg/dl reduction among GA + AA individuals (p < 0.05). These findings demonstrated that vegetarian diet alone was associated with lower HDL-C, no matter the rs1801133 genotype. However, the inclusion of regular exercise predicted much lower levels among GG individuals, whereas levels among GA + AA individuals were relatively higher.


Assuntos
HDL-Colesterol/metabolismo , Dieta Vegetariana , Exercício Físico , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Polimorfismo Genético , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Dieta Vegetariana/estatística & dados numéricos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Taiwan
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